INTS15, A Subunit of the Integrator Complex, Plays a Key Regulatory Role in Cell Cycle and Differentiation

We previously reported that Integrator complex subunit 15 (INTS15) is a causative gene for an autosomal-dominant eye disease named variable panocular malformations (VPMs) and that INTS15 stably interacts with the Integrator complex to support snRNA 3' end processing, thereby controlling mRNA splicing. Here we report another critical function of INTS15 in cell cycle control. HeLa cells and human iPS cells were engineered to overexpress INTS15 expression in a cumate-responsive manner and used to study its role in the regulation of cell cycle and differentiation. INTS15 activates the expression of p53 and p21 to induce G1 arrest when overexpressed. In in vitro differentiation of iPS cells, INTS15 promotes the formation of the three germ layers as well as differentiation into late retinal tissues. Meanwhile, INTS15 knockdown results in defects in G2/M progression and apoptosis. Moreover, INTS15 expression levels vary substantially by cell type and flactuate during the cell cycle. Thus, this study reveals a novel biological aspect of the Integrator complex and demonstrates its potential practical applications.